rs763150678

Variant names:

• chr21-42383138-G-A
• rs763150678
• NM_001256317.3:c.677C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-42383138-G-A
• chr21-42383138-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001256317.3(TMPRSS3):​c.677C>T​(p.Ser226Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S226S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.638
• Publications: 2 publications found

Genes affected

TMPRSS3 (HGNC:11877): (transmembrane serine protease 3) This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a serine protease domain, a transmembrane domain, an LDL receptor-like domain, and a scavenger receptor cysteine-rich domain. Serine proteases are known to be involved in a variety of biological processes, whose malfunction often leads to human diseases and disorders. This gene was identified by its association with both congenital and childhood onset autosomal recessive deafness. This gene is expressed in fetal cochlea and many other tissues, and is thought to be involved in the development and maintenance of the inner ear or the contents of the perilymph and endolymph. This gene was also identified as a tumor-associated gene that is overexpressed in ovarian tumors. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

TMPRSS3 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Trascript score misZ: 0.22926 (below the threshold of 3.09). GenCC associations: The gene is linked to hearing loss, autosomal recessive, autosomal recessive nonsyndromic hearing loss 8, nonsyndromic genetic hearing loss.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.677C>T	p.Ser226Leu	missense_variant	Exon 8 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.677C>T	p.Ser226Leu	missense_variant	Exon 8 of 13		NP_076927.1
TMPRSS3	NM_032405.2	c.677C>T	p.Ser226Leu	missense_variant	Exon 8 of 9		NP_115781.1
TMPRSS3	NM_032404.3	c.296C>T	p.Ser99Leu	missense_variant	Exon 5 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.677C>T	p.Ser226Leu	missense_variant	Exon 8 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251358 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112010

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser226Leu variant in TMPRSS3 has not been previously reported in individua ls with hearing loss, but it has been identified in 1/16508 South Asian chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools an d conservation analyses suggest that the Ser226Leu variant may not impact the pr otein, though this information is not predictive enough to rule out pathogenicit y. In summary, the clinical significance of the Ser226Leu variant is uncertain. -

not provided Uncertain:1

Jan 02, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	.;D;D;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.89	D;.;D;D;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;L;L;.;L
PhyloP100		0.64
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.5	.;D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.019	.;D;D;D;D
Sift4G	Uncertain	0.022	.;D;D;D;D
Polyphen		0.0	B;B;B;.;B
Vest4		0.25, 0.24, 0.24, 0.26
MutPred		0.65		Gain of catalytic residue at S226 (P = 0.0044);Gain of catalytic residue at S226 (P = 0.0044);Gain of catalytic residue at S226 (P = 0.0044);.;Gain of catalytic residue at S226 (P = 0.0044);
MVP		0.54
MPC		0.095
ClinPred		0.11	T
GERP RS		1.6
Varity_R		0.079
gMVP		0.52
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs763150678; hg19: chr21-43803247; COSMIC: COSV52300609; COSMIC: COSV52300609;